Piperidones



wherein R R and R have the meanings given above;

United States Patent Ofilice 3,161,647 Patented Dec. 15, 1964- Thepresent invention concerns a new process for the production ofhydrogenated pyridones as well as the new compounds obtained by thisprocess which have valuable pharmacological properties.

Compounds of the formula R: O H

H20/ \CHC O-R I i-z (I) wherein (a) condensing V (1) one mole of a5-substituted isoxizale of the formula wherein R has the meaning givenabove, in concentrated mineral acids such as concentrated sulfuric acidor poly phosphoric acid at low temperatures or in glacial acetic acid towhich is added a slight amount of mineral acid, e. g. sulfuric acid atlow temperatures, with (2) a compound which can be converted by means ofa mineral acid into a carbonium ion of the formula R3 )0 R1 CH and thenA v (b) dehydrating the resulting intermediate of Formula I by means ofconcentrated mineral acid, preferably sulfuric acid at temperaturesranging from 15 to 30 whereby an unsaturated pyridone of the formulawherein R R R R and R have the meanings given above, is obtained.

However, if R is methyl, only unsaturated pyridones of ,Formula IV, butno corresponding intermediary 4- hydroxy derivative of Formula I can beobtained.

The object of our invention is to produce new compounds of the formulaR4 (V) wherein R R and R are identical or difierent lower alkylradicals, preferably with maximally 5 carbon atoms each, and R is alower alkyl or lower alkenyl radical, preferably with maximally 6 carbonatoms each, a dialkylamino-alkyl radical, a phenylalkyl or aphenylalkenyl radical, the alkyl and alkenyl groups of these radicalshaving at most three carbon atoms each, while the benzene ring of thetwo last-mentioned radicals can be substituted by at most threesubstituents taken from lower alkyl groups, preferably the methyl group,lower alkoxy groups, preferably the methoxy group, and/or halogen atoms,especially fluorine, chlorine or bromine, or by the methylenedioxyradical.

It has now surprisingly been found that this object can be attained andcompounds of the Formula V, which are distinguished from the previouscompounds of the Formula I by the group COCH and by the substituent atthe nitrogen atom, can be obtained by a new process illustrated in thefollowing reaction diagram:

COC a second addition product T compound of Formula V c (a) In the firstreaction step one mole of an unsaturated ketone of the Formula V1 iscondensed at a temperature ranging from 0 to 30 C. preferably from 15 to25 C., with from one mole to a slight excess thereover of a compound ofthe Formula VII, R R R and R having the meanings in Formulas VI and VIIas given under Formula V.

(b) In the second step one mole of diketene is added gradually at atemperature ranging from about 0 to 30 C., preferably from 15 to 25 C.,to each mole of the reaction product resulting from step (a).

(c) In the third step ring closure of the product obtaincd from step (b)is effected either during the addition 1 of the ,diketene or by holdingthe temperature at 15 to 25 C. until the cyclization is complete whichis the case within 5 to 60 minutes. If necessary the reaction iseffected in the presence of a suitable basic condensing agent,preferably triethylamine.

(d) The resulting reaction mixtureis thenconc'entrated by evaporatingthe solvent in a rotary evaporator under sufiiciently reduced pressureat a temperature not higher than 25 C., finally under high vacuum, andthe residue then added dropwise at 20 while stirring, and the mixture isstirred for another 15 minutes. It is then evaporated in a rotaryevaporator at 20 to 25. On adding a little ether to the residue, aproduct crystallizes which is recrystallized from acetone. The1-ethyl-3-acetyl-4-hydroxy-4,6,6- trimethyl-Z-piperidone melts at 134 to136, (yield: 40% of theory).

Example 3 16.5 ml. propylamine and 23 ml. mesityl oxide are Example 1stirred with ml. water for 1% hours. This solution is added dropwisewhile stirring to 10 ml. diketene at a F l m are added to {nesltyl oxldemaximal temperature of The mixture is then imand the mixture is stirredfor 20 m1nutes, slight heat bemediately evaporated i a rotary evaporatorat 20 to mg generated. 15 ml. triethylamme are added and, Wh16finally-under high vacuum A product crystallizes which coolmg Pdllietene added dropvflse at P 15 is recrystallized from acetone. Thel-n-propyl-B-acetyl- The reaction mixture is then stirred for minutesWith- 4 hydroxy 4,6,6 trimethyl 2 pineridone melts at 1 110 out coolingand then evaporated in a rotary evaporator. (yield: of theory) Theresidue crystalhzes from acetone whereupon 1-ethyl- In an analogousmanner as i th foregoing examples Y Y Y T f :Plpendone 15 there areproduced the 3-acetyl-4-hydroxy-4,6,6-trialkyltamed Whl h melts at 3 (y44% of theory) 20 piperidone derivatives of Formula V, whosesubstituents Example 2 in 1-, 4- and 6, 6-positi ons are listed below inthe columns of Table I, entitled R R R and R respectively, and 11.5 ml.mesityl oxide and 6.5 ml. ethylamine are left correspond to thesubstituents defined in the same manner to stand together for 1 hour at30. 8 ml. diketene are in the starting materials of Formulas VI and VII.

TABLE 1 Expl. R1 R2 R3 R4 CH3 i-C3H7 11-C4H9 CHFCHCHT 8 CH3 CH3 CH3--CH=CHz- 9 on. CH; on; cm-Q-cm- 10 CH3 on; om.-- i-C H7CHz-C1I 11 CH3CH3 CH CH=CHCHZ 12 CH3 OH; on; CH3O-CH OH 13 CH3 CH; CH CHr-CH2 14CH3...... CH3 CH F- CHzCH 15 CH3 CH3 on; c1-crn-om 16 CH3 on. CH3 0H2cm-17 CH3 CH3 CH3 c1150 -on2cH2 CH3O 18 CH3 CH3 CH3 CH3O 'CH2CH2 179 CH2;0113.-.-" CH3 (CHa)2N(C 2)a 20 CH3. CH3 n C H CH2-CHZ- l TABLE1Continued Expl. R1 R R R4 44 02H. c211, CH3 oH30-om-om- OCHa 45 n-CaH7n-C3H CHa -CHz-Cflz 46 n-CaH7 n-O3H CH omQ-orm-onr 47 11-051.-.. n-O Hon, OHz-CH2 48 11-03mm. 11-0311.-." CH -CH GH n-C3H 11-C3H1 n-CaH-L.n-Ca v i-C3H7 l-C H7 C2115 n-CuHrs 11-0411..- main.-." 0113mm -omon,-

i-C4HB CH3 CH3 l-C4H9 t-C4H9. CH3 CH3 t-C4H0 i-C n. CH3 CH3 OH3CH=CHOHg11-C5H1| 11CsHu CH3 11-05111 To produce dosage units for peroralapplication, each Example 1 unit containing preferably 100 mg. or 300mg. of active substance of Formula V, the latter is combined e.g. withsolid, pulverulent carriers such as lactose, saccharose, sorbitol,mannite; starches such as potato starch, corn starch or amylopectin,also laminaria powder or citrus pulp powder; cellulose derivatives orgelatine, also lubricants such as magnesium or calcium stearate orpolyethylene glycols of waxy consistency (Carbowaxes) may be added toform tablets or drage centres. The latter are coated, for example, withconcentrated sugar solutions which, e.g. can contain gum arabic, talcumand/ or titanium dioxide, or they are coated with a lacquer dissolved ineasily volatile organic solvents or mixtures of organic solvents.Dyestuffs can be added to these coat ings, for example, to distinguishbetween diiferent contents of active substance. Soft gelatine capsules(pearlshaped closed capsules) and other closed capsules consist, forexample, of a mixture of gelatine and glycerine, and contain, e.g.,mixtures of the active substance with Carbowax, and hard gelatinecapsules contain, for example, granulates of the active substance withsolid, pulverulent carriers such as, e.g., lactose, saocharose,sorbitol, mannite; starches such as potato starch, corn starch oramylopectin, cellulose derivatives or gelatine, as well as magnesiumstearate or stearic acid. Suppositories are employed as dosage units forrectal application. These consist of a combination of the activesubstance with a neutral fatty base, or also gelatine rectal capsulescan be employed which consist of a combination of the active substancewith polyethylene glycols of waxy consistency (Carbowaxes).

Syrups or suspensions for peroral application consist, for example, of asolution containing at least about 2% and at most about by weight ofactive substance, sugar and a mixture of ethanol, water and glycerine asWell as propyleneglycol and, e.g., aroma, saccharine and/ orcarboxymethylcellulose (for suspension purpose).

The following non-limitative examples illustrate the production oftypical forms of application of compounds according to the invention.

Manufacturing instructions for the production of a syrup containing 5%(weight per volume) of active substance of Formula I Active substance g5.0 Saccharine g 0.6 Sugar g 3.0 Glycerine g 5.0 Distilled water g 10.0Aroma g- 0.1 Ethanol 96% ad ml 100.

Sugar and saccharine are dissolved in hot distilled water. On cooling,the solution is made up to weight with water and glycerine is added. Theaqueous solution is poured into the solution of active substance andaroma in about ml. ethanol and then made up to 100 ml. with ethanol.

Example 11 Manufacturing instructions for the production of a suspensioncontaining 5% (weight per volume) of active substance of Formula I Sugarand sorbic acid aredissolved in about ml. boiling distilled water. Thecarboxymet hylcellulose (CMC) is added to the hot solution which isallowed to cool to room temperature while being stirred slowly.

The thoroughly ground active substance and propyleneglycol are'made intoa homogenous paste. Then the cooled CMC-slurry is added undercontinudns'stirring.

After thefaro'ma has been dissolved inethanol it is added to themixture. This is made up to ml. with distilled water.

What is claimed, is:

1. A process for the production of hydrogenated pyridones comprising (a)condensing one mole of an unsaturated ketone of the formula with fromone mole to a slight excess thereover of a compound of the formula inwhich formulas each of R R and R is, independently, alkyl with maximally5 carbon atoms and R is a member selected from the group consisting ofalkyl with maximally 6 carbon atoms, alkenyl of maximally 6 carbonatoms, dialkylaminoalkyl in which each alkyl has at most 3 carbon atoms,phenylalkyl in which alkyl has at most 3 carbon atoms and phenylalkenylin which alkenyl has at most 3 carbon atoms, the benzene ring of the twolast mentioned members being substituted with from 0 to 3 substituentsselected from the group consisting of methyl, methoxy, fluorine,chlorine and bromine and from 0 to 1 methylenedioxy linked with thebenzene ring to form a group of the formula the reaction being carriedout at a temperature ranging from 0 to 30 C.

(b) adding one mole of diketene gradually at a temperature ranging fromabout '0 to 30 C. to each mole of the resulting reaction product (c)heating the reaction mass resulting from step (b) at a temperatureranging from 15 to 25 C. until the cyclization is complete therebyproducing a compound of the formula Q (d) recovering the last mentionedcompound. v

2. A process as described in claim 1 wherein the temperature during step(a) ranges from about 15 to 25 C.

3. A process as described in claim 1 wherein the temperature during step(b) ranges from about 15 to 25 C.

4. A process as described in claim 1 wherein the time of treatment understep (c) ranges from about 0 to minutes.

5. A compound of the formula Bi /OH R2 R4 wherein each of R R and R is,independently, alkyl with maximally 5 carbon atoms and R is a memberselected from the group consisting of alkyl with maximally 6 carbonatoms, alkenyl of maximally 6 carbon atoms, dialkylaminoalkyl in whicheach alkyl has at most 3 carbon atoms, phenylalkyl in which alkyl has atmost 3 carbon atoms and phenylalkenyl in which alkenyl has at most 3carbon atoms, the benzene ring of the two last mentioned members beingsubstituted with from 0 to 3 substituents selected from the groupconsisting of methyl, methoxy, fluorine, chlorine and bromine and from 0to 1 methylened-ioxy linked with the benzene ring to form a group of theformula References Cited in the file of this patent UNITED STATESPATENTS 2,807,585 Gardner et a1 Sept. 24, 1957 2,999,096 Schlesinger eta1. Sept. 5, 1961 3,004,889 Kuna et a1 Oct. 17, 1961 3,024,166 Kuna etal Mar. 6, 1962 Langis June 5, 1962

1. A PROCESS FOR THE PRODUCTION OF HYDROGENATED PYRIODONES COMPRISING(A) CONDENSING ONE MOLE OF AN UNSATURATED KETONE OF THE FORMULA
 5. ACOMPOUND OF THE FORMULA